tbuckley/cabot-search huggingface dataset:
DDDR-10. SIRTUIN 2 INHIBITION SELECTIVELY INDUCES SENESCENCE IN ATRX-DEFICIENT MALIGNANT GLIOMAS BY MODULATING CHROMATIN LANDSCAPES GENOME-WIDE
Authors: Prit Benny Malgulwar, Carla Danussi, Sharvari Dharmaiah, William E Johnson, Arvind Rao, Jason Huse
Journal: Neuro-Oncology (2023)

Abstract Inactivating mutations in ATRX characterize large subgroups of malignant gliomas in adults and children. ATRX deficiency in glioma induces widespread chromatin remodeling, driving transcriptional shifts and oncogenic phenotypes. Effective strategies to therapeutically target these broad epigenomic sequelae remain undeveloped. We utilized integrated mulit-omics and the Broad Institute Connectivity Map (CMAP) to identify drug candidates that could potentially revert ATRX-deficient transcriptional changes. We then employed disease-relevant experimental models to evaluate functional phenotypes, coupling these studies with epigenomic profiling to elucidate molecular mechanim(s). CMAP analysis and transcriptional/epigenomic profiling implicated the Class III HDAC Sirtuin2 (Sirt2) as a central mediator of ATRX-deficient cellular phenotypes and a driver of unfavorable prognosis in ATRX-deficient glioma. Sirt2 inhibitors reverted Atrx-deficient transcriptional signatures in murine neuroprogenitor cells (mNPCs) and impaired cell migration in Atrx/ATRX-deficient mNPCs and human glioma stem cells (GSCs). While effects on cellular proliferation in these contexts were more modest, markers of senescence significantly increased, suggesting that Sirt2 inhibition promotes terminal differentiation in ATRX-deficient glioma. These phenotypic effects were accompanied by genome-wide shifts in enhancer-associated H3K27ac and H4K16ac marks, with the latter in particular demonstrating compelling transcriptional links to Sirt2-dependent phenotypic reversals. Motif analysis of these data identified the transcription factor KLF16 as a mediator of phenotype reversal in Atrx-deficient cells upon Sirt2 inhibition. Finally, Sirt2 inhibition impaired growth and increased senescence in ATRX-deficient GSCs in vivo. Our findings indicate that Sirt2 inhibition selectively targets ATRX-deficient gliomas through global chromatin remodeling, while demonstrating more broadly a viable approach to combat complex epigenetic rewiring in cancer.
RADT-09. CLINICAL OUTCOMES OF FRACTIONATED STEREOTACTIC RADIOTHERAPY FOR INTACT AND POSTOPERATIVE RADIORESISTANT RENAL CELL CARCINOMA AND MELANOMA BRAIN METASTASES
Authors: Ruben Cruz-Chamorro, John Bryant, Casey Liveringhouse, Justyn Nakashima, Jasmine Graham, Shirley Jiang, Daniel Oliver, Kamran Ahmed, Michael A Vogelbaum, Arnold Etame, James Liu, Andre Beer-Furlan, Nam Tran, Hsiang-Hsuan Michael Yu
Journal: Neuro-Oncology (2023)

Abstract PURPOSE Fractionated Stereotactic Radiotherapy (FSRT) may be an optimal strategy for radioresistant renal cell carcinoma (RCC) and melanoma brain metastases (BM). We reviewed our institutional experience of FSRT to intact BM and postoperative cavities for patients with melanoma and RCC. METHODS We retrospectively identified consecutive patients with melanoma and renal cell carcinoma with unresected or resected BM treated with FSRT at our institution from 1/2018 to 1/2021. Time to event outcomes were estimated using the Kaplan-Meier method with log-rank tests and multivariable Cox regression analyses. RESULTS We identified 44 patients with a total of 64 BM: 31 intact (48.4%) and 33 resected BMs (51.6%). Thirty-six (81.8%) were melanoma and eight (18.2%) were RCC. The majority of intact BM (n = 22/31; 71%) and cavities (n = 21/33; 64%) were treated to 30 Gy (24-30) in 5 fractions and 25 Gy (24-35), respectively. Median PTV volume for intact BM was 5.04 cc (1.2-19.8) and for resected BM was 16.7 cc (4.8-89.1). Median interval from planning MRI to FSRT was 10 days (3-28). Median time from surgery to FSRT was 37 days (9-90). At 18.6 months median follow-up, local and intracranial distant failures were observed in 4 and 20 patients, respectively. Our cohort had a local recurrence-free survival (LRFS) of 83% and overall survival (OS) of 57% at 12 months; no difference between primary FSRT versus surgery followed by FSRT (p = 0.93 and p = 0.52, respectively). On MVA, higher FSRT dose was associated with better local control (p = 0.01). Radiation Necrosis (RN) was observed in eight treatment areas (12.5%). Neither resection status (p = 0.99) nor PTV volume (p = 0.61) were associated with RN. CONCLUSION FSRT is associated with low rates of toxicity and clinically significant disease control for both intact and resected melanoma and RCC BM, with higher FSRT dose being correlated with improved control.
EXTH-27. ASSESING THE EFFECT OF ELECTRIC FIELD THERAPY ON PATIENT DERIVED GLIOMA STEM CELL LINES AND GLIOMA INFILTRATING CEREBRAL ORGANOIDS
Authors: Ashwin Narayanan, Jinwei Zhao, Tomisin Olukoga, Christopher Bullock, Richard Fu
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is the most aggressive primary brain tumour in adults. Electric field therapy (EFT) is a new cancer treatment applied after safe maximal tumour resection that interferes with cancer cell division, slowing tumour recurrence and prolonging life. In GBM patients, this therapeutic modality has demonstrated an increase in median survival from ~16 to ~21 months. This study aimed to assess and decipher the effectiveness of EFT on patient-derived glioblastoma stem cell lines (GSC) as well as on advanced Glioma infiltrating cerebral organoid models (GLICOs). To achieve the project goals, we used a novel In-vitro EFT stimulation apparatus to test stimulation parameters on multiple patient-derived GSC lines as well as GLICO models derived from them. We used advanced microscopy and transcriptomic sequencing to visualize and decipher the causal effect of our stimulation regime on the in-vitro models. We observe a strong effect of our EFT regime on multiple GSC lines as well as on GLICOs when compared to their controls. Transcriptomic analysis showed multitude of differentially expressed mRNAs between the treated and control samples with multiple pathways being dysregulated from nuclear proteins, cell mitosis-related events and activation of non-apoptotic mediated programmed cell death pathways indicating a novel mechanism of action. Advanced causal inference studies using the data also provided novel insights on combinatorial therapies that could enhance the efficacy of the treatment. This study provides novel understanding of the mechanism of EFT with potential for optimised treatment regimens for GBM patients.
ANGI-03. NOVEL ROLE OF ENDOTHELIAL CELL AQUAPORIN-1 IN GLIOBLASTOMA VASCULAR PERMEABILITY AND TUMOR-ASSOCIATED EDEMA
Authors: Abigail Cleveland, Menggui Huang, Yi Fan
Journal: Neuro-Oncology (2023)

Abstract Glioblastomas are the most common malignant brain tumors in adults, with a median survival of only 12-15 months. Glioblastomas are marked by an aberrant, leaky vasculature that promotes a hypoxic, immunosuppressive microenvironment. This aberrant vascularity not only affects treatment sensitivity but the integrity of the blood brain barrier (BBB). Disruption of the BBB can lead to increased flow of water into intercellular spaces, causing vasogenic edema. Increased intracranial pressure due to vasogenic edema in glioblastoma patients is a significant cause of morbidity and mortality. Severity of edema not only correlates with patient survival, but causes numerous harmful side effects, such as aphasia, cognitive decline, and acute herniation syndrome. Currently, the mainstay of treatment for brain tumor edema is glucocorticosteroids, such as dexamethasone. However, this treatment causes immune suppression and severe long-term adverse effects. To determine the potential role of vascular endothelial cells (ECs) in edema formation, we performed single cell RNAseq on a genetically engineered glioblastoma mouse model, which recapitulates the edema seen in human patients. We found that ECs from glioblastomas and normal brain tissue had distinct expression patterns, with selective expression of a water channel protein called Aquaporin-1 (AQP1) in glioblastoma ECs. In addition, siRNA-mediated AQP1 knockdown decreased GBM EC monolayer permeability. Inhibiting the water channel function of AQP1 alone through Bacopaside II treatment, however, did not alter EC monolayer permeability. Several tight junctions are downregulated in GBM ECs compared to normal brain ECs, and knocking down AQP1 via siRNA restored expression of the tight junction protein Claudin-5. These data suggest that AQP1 induces brain tumor edema by inhibiting tight junction protein expression via its non-water-channel function and that targeting AQP1 in glioblastoma ECs would be a novel therapeutic strategy to improve the BBB and decrease edema levels in vivo.
INNV-30. DEVELOPMENT AND IMPLEMENTATION OF A NOVEL, BRIEF NEUROCOGNITIVE SCREENING AND REHABILITATION SERVICE IN A CLINICAL NEURO-ONCOLOGY SETTING
Authors: David Sheppard, Myron Goldberg, Tresa McGranahan, Jerome Graber, Vyshak Venur, Karl Cristie Figuracion, Young Bin Song, Jeffrey Wefel, Kyle Noll, Manuel Ferreira, Lia Halasz, Lynne Taylor
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Although neurocognitive dysfunction is common in patients with brain tumors, existing screening methods (e.g., Montreal Cognitive Assessment) lack sensitivity for detecting neurocognitive difficulties. Moreover, existing neurocognitive screens provide only modest clinical utility for characterizing individual neurocognitive strengths/weaknesses critical for treatment planning. METHODS Beginning in February 2023, the Alvord Brain Tumor Center at the University of Washington Medical Center (UWMC) implemented the Rehabilitation Neuropsychology Screening Service (RNSS). The RNSS is an internal outpatient service staffed by a rehabilitation neuropsychologist from the Department of Rehabilitation Medicine at UWMC. Neuro-oncologists and advanced practice providers placed referrals to the RNSS based on clinical need and cognitive symptoms. On average, 1-2 referrals per week were received. RESULTS Patients referred to the RNSS have included those with high- and low-grade gliomas with varying degrees of everyday functioning status (e.g., independence at home, goals to return to work/school) and neurocognitive symptoms. The goal of the RNSS is to explore inclusion and exclusion criteria that optimize patient experience and outcomes while maximizing outreach to patients in need of neurorehabilitation services. The RNSS includes brief, repeatable neuropsychological testing (90-minutes) and patient-reported outcomes (e.g., mood, quality of life). A separate feedback appointment is then held with patients to describe personal neurocognitive strengths/weaknesses and provide neurorehabilitation strategies or rehabilitation resources/referrals based on findings. In select cases, RNSS has served as a triage stage for stepped care towards referrals to a more comprehensive neuropsychological evaluation. CONCLUSION The development and implementation of this novel approach to neurocognitive screening and rehabilitation, including the rationale, workflow of patient care, and expected outcomes, is described. With additional quality assessment/improvement, the RNSS may serve as a model for integrating neurorehabilitation services into existing neuro-oncology clinics, and may be an additional guide for patients and families towards neurorehabilitation resources and education.
BIOM-07. NON-TUMOR PLASMA EXTRACELLULAR VESICLES PREDICT THE OCCURRENCE OF GBM: A MACHINE LEARNING ANALYSIS
Authors: Abudumijiti (Zack) Aibaidula, Abdul Karim Ghaith, Mohamad Bydon, Ian Parney
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Glioblastoma (GBM) is the most common primary malignant brain tumor and has a poor clinical outcome. Extracellular vesicles (EVs) are promising biomarkers to assist the differential diagnosis between pseudoprogression and true tumor progression. We aimed to identify non-tumor plasma EV markers that predicted GBM occurrence using trained multiple tree-based machine learning algorithms. METHODS We included plasma samples of 40 GBM and 40 non-GBM (20 brain metastasis, 20 normal donors). Spectral flow cytometry was performed to determine plasma EV subpopulation frequency based on CD9,CD81,CD63,CD11b,CD45,CD31, and CD41a expression. Multiparametric t-SNE and FlowSOM analysis clustered plasma EVs based on these markers. Decision trees and random forest classifiers were trained and tested to predict the disease status (GBM vs non-GBM) based on plasma EV subpopulations. RESULTS Compared to non-GBM, GBM had increased frequency of CD9+ EVs (64.52% vs 40.69%, p&amp;lt; 0.0001), CD9+CD63-CD81- EVs (54.45% vs 37.26%, p&amp;lt; 0.0001) and myeloid-derived EVs (CD9+CD11b+ EVs, 20.77% vs 12.48%, p = 0.0241). In the decision tree analysis, low frequency of CD9+ EVs was found in 44% of all cases and represented a chance of 75% to be classified as non-GBM cases. An algorithm based on random forest analysis (n = 500 trees) using these markers had a sensitivity of 85.71% and specificity of 77.8% with an overall accuracy of 81.25% for identifying GBM. The frequencies of CD9+, CD9+CD63-CD81-, and CD9+CD63+CD81+ were the most critical factors in predicting GBM diagnosis. FlowSOM analysis identified 20 plasma EV subpopulations but had a lower accuracy (62.5%) when combined with our machine learning algorithm. CONCLUSIONS Non-tumor plasma EV expression profile combined with tree-based machine learning demonstrated high accuracy in predicting patient disease status. CD9+ EV frequency was one of the most promising biomarkers to assist in this diagnosis. We will continue to test our established algorithm and further validate our findings in a larger cohort.
EPID-30. DYSPHAGIA-RELATED HEALTHCARE UTILIZATION AMONG OLDER PATIENTS WITH PRIMARY AND METASTATIC BRAIN TUMORS: A NATIONAL STUDY OF MEDICARE BENEFICIARIES
Authors: David A Leiman, Alice Parish, Seth M Cohen, Donna Niedzwiecki, Margaret O Johnson
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Swallowing dysfunction is common among older adults and the presence of a malignant brain tumor (primary or metastatic) may compound the existing burden of dysphagia in this population. We aimed to characterize the dysphagia-specific healthcare utilization among Medicare beneficiaries with malignant brain tumors. METHODS Using a Medicare 5% limited dataset (2013-2018) and ICD-9/10 codes, we identified beneficiaries (≥ 65 years) with primary malignant brain tumors (PMBTs) as well as the five most common solid tumors metastasizing to the brain (lung, breast, melanoma, renal, and colorectal). Those with disorders predisposing to dysphagia were excluded. Healthcare utilization was quantified using CPT codes for hospitalizations, gastroenterology services (endoscopy [EGD]), nutrition consultation, speech language management, radiographic testing, and enteral feeding access, occurring after cancer diagnosis. Comparisons of utilization by dysphagia status were made using chi-square and Wilcoxon rank-sum tests. RESULTS Among 79,926 beneficiaries, we identified 3,184 (4.0%) with malignant PBTs and 1,033 (1.3%) with brain metastases. Of the total cohort, 4.7% (n=3,777) experienced dysphagia. Whereas, 11.0% (n=349) of those with PMBTs and 7.9% (n=82) with brain metastases experienced dysphagia. Those with PMBTs were diagnosed with dysphagia significantly earlier in their disease course compared to other groups (median 20 vs. 36 vs. 58 days for PMBTs, brain metastases, and no brain metastases, respectively; p&amp;lt; 0.01). Speech pathology services use was highest among PMBT patients compared other groups (36.1%; n=126; p&amp;lt; 0.001). Gastroenterology services utilization overall was high among all groups and enteral feeding tube placement was significantly higher among PMBTs (p&amp;lt; 0.001). CONCLUSIONS Dysphagia increases with age and older patients with brain malignancies are at particularly high risk. Those with PMBTs experience dysphagia earlier in their disease course and dysphagia-related healthcare utilization is higher when compared to other cancers. Our findings have important implications as the number of Medicare beneficiaries is expected to increase.
DDDR-04. TRANSIENT SUPPRESSION OF XPO1 ACTIVITY IS SUFFICIENT FOR SELINEXOR-INDUCED CYTOTOXICITY IN GLIOBLASTOMA CELLS LINES
Authors: Yongjian Tang, Lisa Sprinzen, Yukinori Terada, Russell Pieper
Journal: Neuro-Oncology (2023)

Abstract Inhibitors of the nuclear export protein exportin 1 (XPO1i) show promise in the treatment of leukemias and solid tumors, including brain tumors. XPO1i such as Selinexor reversibly bind and inhibit XPO1 activity, resulting in a lethal nuclear accumulation of a variety of XPO1 substrates. Although XPO1i activity has been suggested to require prolonged suppression of XPO1 activity, this point has not been directly addressed. To do so we generated glioblastoma and patient-derived glioblastoma xenograft cells that express either endogenous wild-type (WT) XPO1 or endogenous WT XPO1 plus a doxycycline-inducible point-mutant form of XPO1 (C528S) that exhibits full XPO1 activity but cannot bind or be inhibited by Selinexor. These cells were then incubated with doxycycline before, or at various time after, the initiation of continuous Selinexor exposure, after which the ability of C528S XPO1 to rescue cells from Selinexor-induced toxicity could be determined. All four glioblastoma cell lines examined were drug-sensitive (IC50 &amp;lt; 600nM) and exhibited a dose-dependent nuclear retention of the XPO1 substrate RanBP1 following Selinexor exposure. Induced expression of C528S led to a doubling of XPO1 protein levels (WT plus C528S), and variable increases in Selinexor IC50, from 3-fold in GBM43 cells to 12,000-fold in LN229 cells. While induction of C528S expression prior to, or up to 8 h after, Selinexor exposure completely prevented Selinexor-induced cytotoxicity, cells could not be rescued after a 24 hr Selinexor exposure. Furthermore, the resistance provided by prolonged expression of C528S, or by shRNA-mediated suppression of XPO1 levels, was nearly 10-fold less than that provided by complete CRISPR-based replacement of WT XPO1 with C528S. These results therefore show that a transient suppression of XPO1 activity is sufficient for Selinexor-induced cytotoxicity in glioblastoma cells, and suggest that the Selinexor-induced lethality results from a combination of loss of XPO1 activity and Selinexor-XPO1 complex formation.
NCOG-16. VALIDATION OF EFFICACY OF CCRT FOLLOWED BY TEMOZOLOMIDE FOR NEWLY DIAGNOSED GBMS: 15-YEAR EXPERIENCE OF A SINGLE INSTITUTION
Authors: Ka Hyen Ko, Ho Kang, Kihwan Hwang, Byung Se Choe, Gheeyoung Choe, Yu Jung Kim, Chag-Yong Kim
Journal: Neuro-Oncology (2023)

Abstract PURPOSE The authors have analyzed the long-term follow-up results of chemotherapy with temozolomide (TMZ) during and after radiotherapy in patients with newly diagnosed glioblastoma (GBM). This study self-validates the effect of a treatment protocol that has been applied at a single institute for more than 18 years. MATERIALS AND METHODS Total 229 patients of newly diagnosed GBM patients who were treated with TMZ during and after radiotherapy from 2004 to 2018 in the authors’ institute were enrolled and analyzed in this retrospective study. Primary outcome was overall survival (OS), and progression-free survival (PFS) was the second outcomes. Long term survivors (LTS) were also reviewed retrospectively. 2021 World Health organization (WHO) classification has been used for this study. RESULTS The median follow-up period was 16.4 months (range, 1.3-171.1). Younger age (&amp;lt; 70 years old), higher KPS score (≥80 and ≥60), gross total resection (GTR), completion of the Stupp protocol, and salvage treatment in patients with the progressive disease showed significantly longer OS times than the other subgroups. Subgroup analysis has been gone through comparing LTS to non-LTS. non-GTR (42% vs. 67.6%, p &amp;lt; 0.001), preop KPS ( &amp;gt;60, 100% vs. 91.1%, p = 0.026) ( &amp;gt;80, 94% vs. 81%, p = 0.027), MGMT promoter methylation (42% vs. 26.3%, p = 0.034) were statistically significant factors that differentiate LTS from non-LTS. In our study, salvage treatment was significantly associated with increased survival in patients with PD. More specifically, if standard treatment was aborted, salvage treatment improved overall survival CONCLUSION Concurrent chemoradiotherapy using TMZ might be still effective for newly diagnosed GBM. Completing the Stupp protocol in patients with newly diagnosed GBM and salvage treatment in patients with the progressive disease might help achieve better survival.
NIMG-42. RADIOIMMUNOMIC SIGNATURES IN PEDIATRIC LOW-GRADE GLIOMA FOR NON-INVASIVE IDENTIFICATION OF IMMUNOTHERAPEUTIC TARGETS
Authors: Anahita Fathi Kazerooni, Adam Kraya, Komal Rathi, Nastaran Khalili, Debanjan Haldar, Ariana Familiar, Meen Chul Kim, Sina Bagheri, Hannah Anderson, Jessica Foster, Phillip Storm, Christos Davatzikos, Jeffrey B Ware, Arastoo Vossough, Adam Resnick, Ali Nabavizadeh
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Tumor immune microenvironment (TIME) plays a key role in response to anti-tumor therapies. Therefore, detailed characterization of TIME is crucial for patient stratification and enrollment onto emerging immunotherapies. As standard-of-care treatments are not feasible or confer devastating long-term morbidity for pediatric low-grade glioma (pLGG), non-invasive quantification of the TIME using radiomic analysis, may guide treatment decisions. On the largest available transcriptomic and imaging data in pLGGs, provided through Children’s Brain Tumor Network (CBTN), this data-driven study aims to discover immunological profiles of pLGG that are meaningfully related to biomarkers of tumor immune response, and radioimmunomic signatures that are predictive of immunological profiles. METHODS Enrichment of immune and stromal cell types and pathways in 502 subjects were inferred using xCell algorithm applied to transcriptomic data and the tumors were then clustered via consensus clustering approach. Tumor inflammation signature (TIS), as a biomarker of response to anti-PD-1 blockade, was compared across the immunological clusters. Quantitative radiomic features were extracted from the segmented tumor regions on multiparametric MRI scans of 155/502 patients. Cross-validated support vector machines with forward feature selection were trained on radiomic features using one-versus-the-rest approach to predict the immunological groups. RESULTS Three immunological clusters, i.e., immune-cold, -altered, and -hot were found, with different levels of enrichment in immune and microenvironment scores, CD4 T-cells, and macrophages. Significantly higher TIS values were found in immune-hot and -altered compared to immune-cold tumors (p= 1.2e-8 and p= 7e-16, respectively). Radioimmunomic models yielded average AUC of 0.75 for one-versus-the-rest differentiation of the immunological clusters. CONCLUSIONS The proposed analysis revealed three distinct immunological groups in pLGGs, with immune-hot tumors more likely to respond favorably to immunotherapies. Furthermore, non-invasive radioimmunomic signatures were shown to potentially stratify the patients based on their TIME, which upon further development and validation, could inform treatments for pLGGs.